Ophthalmic devices for delivery of beneficial agents

ABSTRACT

Contact lenses comprising phosphorylcholine groups release beneficial polyionic or guanidinium-containing agents.

This application is a divisional of U.S. patent application Ser. No.14/109,977, filed Dec. 18, 2013, which claims the benefit under 35U.S.C. §119(e) of prior U.S. Provisional Patent Application No.61/740,617, filed Dec. 21, 2012, which is incorporated in its entiretyby reference herein.

BACKGROUND

The field of the disclosure is ophthalmic devices for administeringbeneficial agents.

Contact lenses for administering ophthalmic drugs and other beneficialagents to the ocular tissue of a patient have been described. Forexample, the anionic contact lens material, etafilcon A, has been usedin clinical studies to deliver or administer ketotifen, an anti-allergydrug used in the treatment of allergic conjunctivitis (seeClinicalTrials.gov NCT00569777). A problem associated with some oculardelivery devices is that they can be limited in the type of beneficialagent that the device is capable of administering. Another problemassociated with some ocular drug delivery devices is that they involvecomplex manufacturing methods which are not amenable to large-scalemanufacturing operations. We have discovered improved methods ofmanufacturing beneficial agent-releasing contact lenses that addressthese problems.

Contact lens packages including a sealed receptacle that contains acontact lens made of a silicone hydrogel copolymer in a sterile solutionwhich comprises a stabilizing agent which can form an ionic complex orhydrogen bond with the hydrogel copolymer, have been described in U.S.Pat. Publ. No. 2007/0149428. A packaging system and method for thestorage of an ionic hydrogel lens that uses an aqueous packing solutionwhich includes a phosphorylcholine polymer, and which further caninclude a buffering agent, have been described in U.S. Pat. Publ. No.2009/0100801. Other background publications include U.S. Pat. Publ. No.2008/0085922, U.S. Pat. Publ. No. 2007/0265247, U.S. Pat. Publ. No.2007/20100239637, U.S. Pat. Publ. No. 2008/0124376, U.S. Pat. No.7,841,716, Karlgard et al, Int J Pharm (2003) 257:141-51 and Soluri etal., Optom Vis Sci (2012) 89:1140-1149.

SUMMARY

In one aspect, the invention provides a contact lens that comprises ahydrogel comprising integral phosphorylcholine groups and an ionicagent. Advantageously the ionic agent is electrostatically bound to thephosphorylcholine groups and releases from the lens upon wear by apatient. The ionic agent is polyionic or comprises at least oneguanidinium group or is both polyionic and comprises at least oneguanidinium group.

In a further aspect, the invention provides a method of manufacturing acontact lens. The method comprises polymerizing a monomer mixturecomprising 2-methacryloyloxyethyl phosphorylcholine (MPC) to provide anon-hydrated lens-shaped polymerization product, immersing thenon-hydrated lens-shaped polymerization product in a package containinga packaging solution comprising an ionic agent, and sealing the package.Exemplary monomer mixtures comprise 10 wt. % to 20 wt. % MPC. Exemplaryionic agents are polyionic and/or comprises at least one guanidiniumgroup. The method may further comprise autoclaving the sealed package.

DETAILED DESCRIPTION

We have discovered unique properties of phosphorylcholine(PC)-containing hydrogel contact lenses which can be utilized to deliverbeneficial ionic agents to ocular tissue. The present disclosure isdirected to an ophthalmic device comprising a hydrogel comprisingintegral PC groups and a releasable ionic agent electrostatically boundto the PC groups. Phosphorylcholine is zwitterionic, containing both anegative charge and a positive charge at relatively close proximity, andthus would be expected to act as a net-neutral molecule. However, wehave found that it can be used to attach to and release both anionic andcationic agents. In specific examples, the ionic agent is polyionicand/or comprises at least one guanidinium cation. Contact lenses areexemplified herein, however other types of ophthalmic devices made fromhydrogels, such as ocular inserts, ocular bandages, and intraocularlenses can be made in accordance with the present disclosure. Theophthalmic device is provided unworn (i.e. it is a new device, nothaving been previously used by a patient) sealed in a package, such as ablister package, glass vial, or other suitable package, containing apackaging solution in which the ophthalmic device is immersed.

The hydrogel can be manufactured by polymerizing a monomer mixture toform a polymerization product, and hydrating the polymerization productto obtain the hydrogel. As used herein, the term “monomer mixture”refers to a mixture of polymerizable monomers together with anyadditional ingredients, including non-polymerizable ingredients, whichare subjected to polymerization conditions to form a polymerizationproduct. In the case of contact lenses, so-called “conventionalhydrogels” are typically formed from a monomer mixture comprising ahydrophilic monomer such as 2-hydroxyethyl methacrylate (HEMA) or vinylalcohol, together with a cross-linking agent, optionally in combinationwith other monomers, and containing no siloxane (i.e. a moleculecomprising at least one Si—O group). A silicone hydrogel is formed froma monomer mixture that comprises at least one polymerizable siloxanemonomer. The term “monomer” refers to any molecule capable of reactingin a polymerization reaction with other molecules that are the same ordifferent, to form a polymer or copolymer. Thus, the term encompassespolymerizable pre-polymers and macromers, there being no size-constraintof the monomer unless indicated otherwise.

The hydrogel ophthalmic device comprises integral PC groups, meaningthat the PC groups are covalently attached to the polymer matrix of thehydrogel. The hydrogel may include additional integral ionic componentsthat may electrostatically bind to the ionic agent provided that asignificant amount of the ionic agent binds to the PC groups asdetermined using an in vitro uptake assay as described below. In someexamples, the phosphorylcholine groups provide the only integral ionicgroups of the hydrogel. In one example the monomer mixture used to makethe hydrogel comprises a polymerizable monomer having a PC group. Anexemplary monomer is 2-methacryloyloxyethyl phosphorylcholine (MPC). Ina specific example, the monomer mixture comprises at least 5, 10, or15%, and up to about 20, 30, or 40% MPC, where percentages are weightpercentages based on the total weight of all polymerizable components inthe monomer mixture (i.e. excluding non-polymerizable components such asdiluents, etc.). Omalfilcon A contact lenses, sold under the brand nameProclear, are made from polymerization of a monomer mixture comprisingabout 83 wt. % HEMA, about 16 wt. % MPC, about 1 wt. % ethyleneglycoldimethacrylate (EGDMA), and a tinting agent. Silicone monomerscomprising PC groups can also be used to prepare silicone hydrogels (seee.g. US Pat. Publ. No. 2012/0136087). Alternatively, or in addition toincluding a PC-containing monomer in the monomer mixture a hydrogelcomprising integral PC groups may be prepared by attaching PC to analready cured polymerization product or hydrogel (see e.g. U.S. Pat. No.5,422,402). The amount of integral PC groups incorporated into thehydrogel can be adjusted to provide desirable uptake and releaseproperties for a selected ionic agent. In some examples, the hydrogelcomprises at least 2, 5, 10, or 15 wt. % and up to about 20, 25, 30, or35 wt. % of PC groups, where wt. % is based on the total weight of theintegral components of the non-hydrated hydrogel, and 182 is taken asthe molecular weight for each PC group (i.e. each —PO₄C₂H₄N(CH₃)₃).

All percentages provided herein are percentage by weight unlessindicated otherwise. Throughout this disclosure, when a series of lowerlimit ranges and a series of upper limit ranges are provided, allcombinations of the provided ranges are contemplated as if eachcombination were specifically listed. For example, in the listing of PCgroup weight percentages provided in the preceding paragraph, all 16possible ranges of weight percentages are contemplated (i.e. 2-20 wt. %,5-20 wt. % . . . 15-30 wt. %, and 15-35 wt. %). Further, throughout thisdisclosure when a series of values is presented with a unit ofmeasurement following the last value of the series, the unit ofmeasurement is intended to implicitly follow each preceding value in theseries unless context indicates otherwise. For example, in the previouslisting of PC group weight percent ranges, it is intended that the unitof measurement “wt. %” implicitly follows the values of 2, 5, 10, 20,25, and 30. Also, throughout this disclosure, when a series of values ispresented with a qualifier preceding the first value, the qualifier isintended to implicitly precede each value in the series unless contextdictates otherwise. For example, for the values of the previous listingof PC group weight percentages, it is intended that the qualifier “atleast” implicitly precedes 5, 10 and 15, and the qualifier “to about”implicitly precedes 25, 30 and 35. Additionally, throughout thisdisclosure a reference to “examples”, “one example”, “a specificexample” or similar phrase, is intended to introduce a feature orfeatures of the contact lens, monomer mixture, ionic agent, packagingsolution, method of manufacture, etc. (depending on context) that can becombined with any combination of previously-described orsubsequently-described examples (i.e. features), unless a particularcombination of features is mutually exclusive, or if context indicatesotherwise.

The remaining components of the monomer mixture, the method ofpolymerizing the monomer mixture to make a polymerization product, andthe method of hydrating the polymerization product to make a hydrogelcan be conventional. Exemplary monomer mixture components andpolymerization methods are described in U.S. Pat. No. 6,867,245, toIwata et al., U.S. Pat. No. 8,129,442 to Ueyama et al., U.S. Pat. No.4,889,664 to Kindt-Larsen et al., U.S. Pat. No. 3,630,200 to Higuchi,and U.S. Pat. No. 6,217,896 to Benjamin, and WO 2012/118680 to Liu etal, each incorporated herein by reference. In the case of contactlenses, the monomer mixture is filled into a contact lens mold, which istypically made from a thermoplastic polymer such as polypropylene.Typically, a first mold member defining the front surface of the contactlens, referred to as a “female mold member”, is filled with an amount ofthe monomer mixture sufficient to form a single lens-shapedpolymerization product. A second mold member defining the back (i.e.eye-contacting) surface of the contact lens, referred to as the “malemold member”, is coupled to the female mold member to form a moldassembly having a lens-shaped cavity with the amount of monomer mixturein between the two mold members. The monomer mixture within the contactlens mold assembly is then polymerized using any suitable curing method.Typically, the monomer mixture is exposed to polymerizing amounts ofheat or ultraviolet light (UV). In the case of UV-curing, also referredto as photopolymerization, the monomer mixture typically comprises aphotoinitiator such as benzoin methyl ether, 1-hydroxycyclohexylphenylketone, Darocur or Irgacur (available from Ciba Specialty Chemicals).Photopolymerization methods for contact lenses are described in U.S.Pat. No. 5,760,100. In the case of heat-curing, also referred to asthermal curing, the monomer mixture typically comprises a thermalinitiator. Exemplary thermal initiators include2,2′-azobis(2,4-dimethylpentanenitrile) (V-52),2,2′-Azobis(2-methylpropanenitrile) (V-64), and 1,1′-azobis(cyanocyclohexane) (V-88).

After cure, the mold is opened and the resulting lens-shapedpolymerization product is either mechanically removed from the mold(i.e. dry-delensed) or is wet-delensed by immersing the mold in a liquiduntil the polymeric lens body hydrates and floats off of the mold. Afterdelensing, the polymeric lens body may be washed to hydrate the lensand/or remove extractable components from the lens, or the lens may beplaced directly into its final package containing a packaging solutionwithout a post-delensing washing step. Thus, in one example, the lens isdry when placed into its final package. In another example, the lens maybe partially or fully hydrated when placed in its final package. Thepackage is then sealed and optionally sterilized. Suitable sterilizationmethods include autoclaving, gamma radiation, e-beam radiation,ultraviolet radiation, etc. In some examples, the hydrogel and packagingsolution may be manufactured and combined using sterile conditionsmaking a post-packaging sterilization step unnecessary.

The package may be a hermetically sealed blister-pack, in which aconcave well containing a contact lens is covered by a metal or plasticsheet adapted for peeling in order to open the blister-pack. The packagemay be any other suitable inert packaging material providing areasonable degree of protection to the lens, such as a glass vial or apackage made from a plastic such as polyalkylene (e.g., polyethylene orpolypropylene), PVC, polyamide, and the like. Generally, the finalmanufactured product includes at least a sealed package containing anunused contact lens immersed in an aqueous packaging solution as furtherexemplified herein.

Typically, the ionic agent will be bound to the hydrogel simply bypreparing a packaging solution comprising the ionic agent and immersinga hydrogel or polymerization product comprising integral PC groups intothe packaging solution. The PC groups of the hydrogel attract andelectrostatically bind to the ionic agent. Alternatively, oradditionally, the ionic agent can be incorporated into a hydrogel byadding the agent into the monomer mixture used to form thepolymerization product. The polymerization product is then packaged witha packaging solution either containing no ionic agent or containingadditional ionic agent.

An ionic agent is considered to electrostatically bind to the PC groupsof the hydrogel if the hydrogel takes up a significantly higher amountof the ionic agent compared to a hydrogel of substantially the same sizeand dimensions lacking the PC groups, but otherwise comprising the samecomponents, as measured using an uptake assay substantially as describedin Example 1 below. For example, polymacon 38 contact lenses, sold underthe brand name Biomedics 38, are made from the polymerization of HEMAand EGDMA and comprise the same tinting agent as Proclear 1-Day lenses,and thus are comparable lenses for assessing electrostatic binding of anionic agent to Proclear lenses. In some examples, a hydrogel comprisingintegral PC groups takes up at least 20, 50, 100, or 200 wt. % more ofthe ionic agent than a comparative lens lacking the PC groups.Typically, in the case of contact lenses, the amount of ionic agentbound is at least 10, 20, 25, 50, 75, or 100 μg/lens and up to about150, 200, 250, 300 μg/lens or more. The ionic agent is considered“releasable” if at least 10% of the agent releases from the hydrogelwithin 24 hours when tested in an in vitro release assay substantiallyas described in Example 1 below. In various examples, at least 20, 40,60 or 80% of the agent releases from the hydrogel by 24 hours.

We have found that hydrogels comprising integral PC groups have uniqueuptake and release properties of agents comprising one or more cationicguanidinium groups. As used herein, the term “guanidinium group” refersto a positively charged group comprising a central carbon atomcovalently bonded to three nitrogen atoms, with a double bond betweenone of the nitrogen atoms and the central carbon. Exemplary beneficialagents for ophthalmic applications that comprise at least oneguanidinium group include antihistamines such as epinastine andemedastine; glaucoma drugs such as apraclonidine and brimonidine;guanine derivative antiviral agents such as ganciclovir andvalganciclovir; arginine-containing antimicrobial peptides such as thedefensins and indolicidin; and biguanide-based antimicrobial agents suchas chlorhexidine, alexidine, and polyhexamethylene biguanide (PHMB).References herein to a specific ionic agent are intended to encompassthe agent and any of its ophthalmically-acceptable salts. For example,as used herein, the term “epinastine” refers to epinastine as well asepinastine hydrochloride. In various examples, the ionic agent comprisesat least 1, 2, 4, and up to about 10, 15, 20, or more guanidiniumgroups. In other examples, the ionic agent comprises at least 1, 2, 4,and up to about 10, 15, 20, 50 or more biguanide groups. In yet anotherexample the ionic agent comprises or consists of at least 1, 2, 4, andup to about 10, 15, 20, or more arginine groups. In such example, theionic agent may be a naturally-occurring peptide or synthetic peptide,particularly an antimicrobial peptide. In a specific example, thepeptide is polyarginine.

In another example, the ionic agent is a polymer. The polymer may beanionic, cationic, or zwitterionic provided that it electrostaticallybinds the PC groups of the hydrogel and is releasable. In some examplesthe polymer is cationic and comprises at least 4, 6, 8, 10, 15, 20 ormore cationic groups. In other examples, the polymer is anionic andcomprises at least 4, 6, 8, 10, 15, 20 or more anionic groups. Exemplarycationic polymers include epsilon polylysine (εPLL), antimicrobialpeptides which comprise multiple arginine and/or lysine groups, PHMB,and quaternary ammonium compounds (i.e. polyquats). Exemplary anionicpolymers include sulfonate-group containing polymers such as polystyrenesulfonate and anionic polysaccharides such as alginate, xanthan gum,gellan gum, and hyaluronic acid. We have found that polystyrenesulfonate (PSS) can significantly decrease the coefficient of frictionof Proclear lenses. Thus in one example the agent is polystyrenesulfonate. In specific examples, the agent is a polystyrene sulfonatehaving an average molecular weight of from about 50K, 75K, 100K or 500Kup to about 1M, 2M, or 4M. In further examples, the PSS is provided in apackaging solution at a concentration of about 50, 250, or 500 ppm up toabout 1000, 2500 or 5000 ppm. We have also found that polyquaternium-55,sold under the tradename Styleze® W-20, significantly decreases thecoefficient of friction of omalfilcon A contact lenses even afterwashing the lenses overnight in PBS. Thus, in a specific example, theionic agent is polyquaternium-55 and is included in the packagingsolution at a concentration of about 0.01, 0.05, or 0.1% up to about0.5%, 1.0%, or 2.0%.

We have shown that hydrogels comprising integral PC groups can sustainrelease of certain ionic agents for 12 hours or more. This may bebeneficial for therapeutic applications where continuous drug deliveryis advantageous over delivery by ophthalmic drops. As used herein, ahydrogel comprising integral PC groups is said to exhibit “sustainedrelease” of an ionic agent for at least a given duration of time ifthere is a significant increase in cumulative amount of the ionic agentreleased between the end of that given duration of time and the nexttime duration of time tested as determined in an in vitro release assaysubstantially as described in Example 1. For example, if a hydrogelreleases 30 μg of an ionic agent between 0-2 hours, and releases anadditional 30 μg of the ionic agent between 2-6 hours, as determinedusing the in vitro release assay, the hydrogel is said to sustainrelease of the ionic agent for at least 2 hours. In some examples, thehydrogel sustains release of the ionic agent for at least 6 hours or 24hours. The amount of PC in the lens and the concentration of the ionicagent in the packaging solution (and/or in the monomer mixture) can bebalanced to provide desirable release profiles.

Example 1 demonstrates the unique release properties of a hydrogelcontact lens comprising integral PC groups, Proclear, compared to anonionic silicone hydrogel lens, an ionic silicone hydrogel lens, and aconventional ionic hydrogel lens comprising HEMA and about 1.8 wt. %methacrylic acid. This example evaluated the release of PHMB, apolycationic polymer used to treat Ancanthamoeba infections, a conditionwhich can lead to blindness if left untreated. The nonionic siliconehydrogel lens took up less than 10% the amount of PHMB that was taken upby the Proclear lens and released about 50% of its PHMB within the firsttwo hours of the release assay; it exhibited no significant PHMB releasebeyond the two hour time point. In contrast, the PC-containing lensessustained PHMB release for at least 24 hours. Although the conventionalionic hydrogel lens took up about 30% more PHMB than the Proclear lens,it evidently bound to PHMB much more strongly, as it released only about40% or less of the amount released by the Proclear lenses at each of thetime points tested. Unlike anionic lenses, hydrogels comprising integralPC-groups can also sustain release of an anionic polymer, asdemonstrated with polystyrene sulfonate in Example 8 below. Thus, invarious examples, the hydrogel comprising integral phosphorylcholinegroups sustains release of an ionic agent for at least 2, 6, or 24hours, as determined using a release assay substantially as described inExample 1. In some examples, the ionic agent is a cationic polymer. Inother examples, the ionic agent is an anionic polymer.

We have found that by decreasing the ionic strength of the packagingsolution from what is conventionally used for ophthalmic devices, suchas contact lenses, uptake of an ionic agent by a hydrogel comprisingintegral PC groups can be significantly increased. For example, hydratedProclear contact lenses were packaged and autoclaved in PBS having anionic strength of about 0.2 and comprising 500 ppm εPLL, anantimicrobial peptide. These lenses took up an average of 5 μg of theεPLL/lens. The lenses were found to have no antimicrobial activityagainst the ocular pathogen, Serratia marcescens. In contrast, the sameProclear lenses packaged and autoclaved in TRIS buffer with 2% sorbitol,which has an ionic strength of about 0.02, took up an average of about120 μg εPLL/lens and resulted in about a 4-log kill of Serratiamarcescens. Thus, in various examples, the packaging solution has anionic strength of less than about 0.15, 0.10, or 0.05 as calculated bythe equation:

$I = {\frac{1}{2}{\sum\limits_{i = 1}^{n}\;{c_{i}z_{i}^{2}}}}$where c_(i) is the molar concentration of ion i (mol·dm⁻³), z_(i) is thecharge number of that ion and the sum is taken over all ions in thesolution. To reduce ionic strength while maintaining proper osmolalityin the range of about 200 mOsm/kg to about 400 mOsm/kg, sodium chloride,which is commonly used as a tonicity agent in contact lens packagingsolutions, can be replaced with a non-electrolyte tonicity agent, suchas sorbitol, as indicated above. Other non-electrolyte tonicity agentsthat can be used in the packaging solution include mannitol, sucrose,glycerol, propylene glycol, xylitol, inositol, polyethylene glycols,polypropylene glycols, and mixtures thereof. In some examples, theosmolality of the packaging solution is at least about 250 or 270mOsm/kg up to about 310, or 350 mOsm/kg. In some examples, the packagingsolution consists, or consists essentially, of an aqueous solution of abuffer, a tonicity agent, and the ionic agent. In other examples, thepackaging solution contains additional agents such as an antimicrobialagent, a comfort agent, a hydrophilic polymer, or a surfactant or otheradditive that prevents the lens from sticking to the package. Thepackaging solution typically has a pH in the range of about 6.8 or 7.0up to about 7.8 or 8.0.

Hydrogel contact lenses comprising integral PC groups can uptake andrelease ionic agents without significantly altering the dimensions ofthe lens (e.g. lens diameter and base curve), lens clarity (i.e. thelenses are optically clear, having at least 93%, 95%, or 97% lighttransmittance between 380 nm to 780 nm as measured in accordance withISO 18369), or physical properties such as Young's Modulus or tensilestrength.

In various examples the contact lens is an extended-wear contact lenswhich a patient wears continuously for at least 24 hours, 5 days, 7days, or 14 days. In another example the contact lens is adaily-disposable lens which is worn by a patient during waking hours,removed and discarded prior to sleep, and replaced by a new, unworn lenseach day. In a further example, the contact lens is a daily-wear lenswhich a patient wears during the day and stores each night in a solutionintended for contact lens storage. In such example, the contact lensstorage solution may comprise an additional dose of the ionic agentwhich incorporates into the contact lens and electrostatically binds tothe PC groups during the overnight storage, thereby replenishing ionicagent that was released from the previous daytime wear of the lens.

We have found that uptake of certain ionic agents is significantlyhigher if the polymerization product is non-hydrated when immersed intoa packaging solution comprising the anionic agent. The higher uptakeremains even after autoclaving the packaged hydrogel. Thus, in aspecific example, the method comprises polymerizing a monomer mixturecomprising MPC in a contact lens mold to provide a non-hydratedlens-shaped polymerization product, removing the polymerization productfrom the mold, immersing the non-hydrated lens-shaped polymerizationproduct in a package containing a packaging solution comprising an ionicagent, and sealing the package, wherein the ionic agentelectrostatically attaches to phosphorylcholine groups on the MPC. Invarious examples the ionic agent is polyionic or comprises at least oneguanidinium group or is both polyionic and comprises at least oneguanidinium group. Any of the previously-described specific ionicagents, classes of ionic agents, and amounts thereof may be included inthe packaging solution. The method may comprise the further step ofautoclaving the sealed package.

The ophthalmic devices described herein can be used in a method ofadministering a beneficial agent to a patient in need of the agent. Themethod comprises providing the patient with a hydrogel comprisingintegral phosphorylcholine groups and a releasable ionic agentelectrostatically bound to the phosphorylcholine groups. The ionic agentis polyionic or comprises at least one guanidinium group or is bothpolyionic and comprises at least one guanidinium group. In variousexamples, the beneficial agent delivered by the ophthalmic device isindicated for the prevention or treatment of an ophthalmic disease,disorder, or infection with which the patient has been diagnosed or ofwhich the patient has been determined to be at risk. For example, theagent may be an antihistamine such as epinastine or emedastine for thetreatment of allergic conjunctivitis. In another example the agent is aglaucoma drug such as apraclonidine or brimonidine. In a further examplethe agent is a guanine derivative antiviral agent such as ganciclovir orvalganciclovir for the treatment of herpetic keratitis or other viralinfection. In yet another example, the agent is an antimicrobial agentindicated for the treatment of microbial keratitis, such as a defensin,indolicidin, ε-PLL, chlorhexidine, or PHMB. In still a further example,the agent is a comfort polymer used for the treatment of symptoms of dryeye disease or contact lens intolerance. In various examples theophthalmic device is selected from a contact lens, an ocular insert, anocular bandage, and an intraocular lens.

The following Examples illustrate certain aspects and advantages of thepresent invention, which should be understood not to be limited thereby.

Example 1 Uptake and Release of PHMB by MPC-Containing Contact Lenses

The uptake and release of PHMB from commercially-available Proclear1-Day (omalfilcon A) contact lenses was compared with acommercially-available, non-ionic silicone hydrogel lens (Biofinity), acommercially-available, ionic HEMA lens comprising about 1.8 wt. %methacrylic acid (Biomedics 55), and an ionic silicon hydrogel lenscomprising about 1.8 wt. % methacrylic acid (SiHy-MA). Proclear lensesare prepared from a monomer mixture comprising about 83 wt. %2-hydroxyethylmethacrylate (HEMA), about 16 wt. % 2-methacryloyloxyethylphosphorylcholine (MPC), and about 1% cross-linking agent, where wt. %is based on the total weight of polymerizable monomers in the monomermixture.

Ionic Agent Uptake Assay:

The lenses were removed from their packaging, vortexed in deionizedwater three times, then allowed to equilibrate overnight in deionizedwater at room temperature. The lenses were then placed in 6 ml glassvials containing 1.2 ml of 500 ppm PHMB in PBS. Unless indicatedotherwise, references herein to PBS mean an aqueous solution of 0.83 wt.% NaCl, 0.03 wt. % sodium phosphate monobasic, and 0.24% sodiumphosphate dibasic having a pH of 7.3. The samples in vials were kept ona shaker and maintained at 25° C. for the duration of the uptake. At 2,6, and 24 hours, and once a day thereafter until uptake was complete,the packing solution was tested by HPLC for PHMB concentration. Uptakewas considered complete when the PHMB concentration of the packingsolution stopped decreasing. After uptake was complete, the lenses weretested for PHMB release as described below. Controls of PHMB solutionwithout lenses were also tested.

Ionic Agent Release Assay:

Cumulative release of PHMB from the lenses was tested by transferringeach lens to 1.0 ml ISO 10344 release media in 6 ml lens vials. Samplesin vials were kept in a heated shaker at 37° C. for the duration ofrelease. At 2, 6, and 24 hours, and once a day thereafter, the packingsolution was tested by HPLC for amount of PHMB released and the lenseswere transferred to fresh vials of ISO10344 for continued PHMB release.Tables 1 and 2 summarize the uptake and release data, respectively.

TABLE 1 PHMB uptake (μg) Lens 2 hr 6 hr 24 hr 48 hr 72 hr 96 hrBiofinity 36 44 40 39 41 29 Proclear 292 383 372 419 418 420 Biomedics55 366 523 543 589 589 589 SiHyMA 224 358 418 493 495 494

TABLE 2 cumulative PHMB release (μg (%)) Lens 2 hr 6 hr 24 hr 48 hr 96hr Biofinity  17 (39) 17 (39) 17 (39) 17 (39) 17 (39) Proclear 35 (9) 68(18) 85 (22) 99 (26) 99 (26) Biomedics 55 12 (2) 24 (5)  33 (6)  41 (8) 41 (8)  SiHy-MA 16 (5) 26 (7)  32 (9)  36 (10) 36 (10)

By comparison, the same experiment was carried out except that thelenses were packaged with 500 ppm PQ1 in PBS. The Proclear lenses tookup an average of 11 μg PQ1, whereas the Biomedics 55 lenses took up anaverage 282 μg PQ1.

Example 2 Uptake of Epinastine by MPC-Containing Contact Lenses

Uptake of epinastine from Proclear contact lenses was compared to uptakeby a non-ionic silicone hydrogel lens (Biofinity) using substantiallythe same methods as described in Example 1, except that the uptakesolution consisted of 50 ppm epinastine solution in TRIS buffer with 3%sorbitol (0.02% TRIS(hydroxymethyl)amino methane, 0.26% trizmahydrochloride, 2.85% sorbitol, and 94.97% deionized H₂O;“Tris-Sorbitol). The Proclear lenses took up an average of about 38 μgepinastine, whereas the Biofinity lenses took up an average of about 14μg epinastine.

Example 3 Uptake of Cromolyn: Dry Vs Wet Loading

The ability of hydrated and non-hydrated (dry) Proclear lenses to takeup olopatadine, ketotifen, and cromolyn was evaluated. At physiologicalpH, olopatadine is zwitterionic, ketotifen is positively charged, andcromolyn is negatively charged. Each drug was prepared at low and highconcentrations: 25 μg/ml and 250 μg/ml ketotifen in borate buffer (pH7.51), 200 μg/ml and 1000 μg/ml olopatadine in PBS, and 400 μg/ml and2000 μg/ml cromolyn in PBS. The hydrated Proclear lenses were removedfrom their packages and washed with PBS as described in Example 1,packaged in 3 ml of each drug solution, and autoclaved. The dry lenseswere removed from their original molds, packaged with 3 ml of each drugsolution without any intermediate hydration step and autoclaved. Forcontrols, each drug solution was packaged without a lens and autoclaved.After autoclave, the amount of drug in each packaging solution wasmeasured by HPLC. Table 3 shows the average drug uptake by each lens(n=3), which was calculated as the difference between the controlpackaging solution and the lens packaging solution. The % increase ordecrease in drug loading by dry lenses compared to wet lenses is shown.The dry lenses took up significantly more of the negatively chargeddrug, cromolyn, at both the low and high concentrations of the drug.

TABLE 3 Drug Uptake (μg) % Δ Dry Drug Dry Lens Wet Lens vs Wet  25 μg/mlketotifen 10 12 −17%  250 μg/ml ketotifen 115 122 −6%  200 μg/mlolopatadine 52 45 16% 1000 μg/ml olopatadine 215 202 6%  400 μg/mlcromolyn 47 32 47% 2000 μg/ml cromolyn 155 81 91%

Example 4 Uptake of εPLL in Low Ionic Strength Packaging Solution

The uptake and release of εPLL from non-hydrated (i.e. dry) Proclearlenses was evaluated. The εPLL (Chisso Corporation, Tokyo, Japan) wasprepared at a concentration of 500 ppm in three different buffers, PBS,TRIS buffered saline (0.023% tris(hydroxymethyl)methylamine, 0.544%trizma hydrochloride, 0.819% NaCl; TBS), or Tris-sorbitol. Lenses wereindividually packaged, in triplicate, in 1.2 ml of each εPLL preparationand autoclaved. Additionally, vials containing 1.2 ml 500 ppm εPLL ineach buffer with no lens (control vials) were also autoclaved. Theamounts of εPLL present in the post-autoclave solution of the test lensvials and in the control vial were determined by cationic size exclusionchromatography using a sample injection volume of 5 μl, a Water AcquityUPLC BEH 125 SEC 1.7 μm 4.6×150 mm at room temperature, and a flow rateof 0.4 ml/min using 90% 0.2M NaCl/0.1% TFA in H₂0: 10% ACNisocratically. The average of the amount of εPLL taken up by each testlens (n=3) was calculated by subtracting the amount of εPLL present inthe post-autoclave solution of the test lens vial from the amount ofεPLL present in the control vial. Lenses packaged with 500 ppm εPLL inPBS took up an average of 88 μg εPLL. Lenses packaged with 500 ppm εPLLin TBS took up 47 μg εPLL, and lenses packaged with 500 ppm εPLL inTris-sorbitol took up 208 μg εPLL.

Example 5 Uptake of Anionic Polymer by Hydrated and Non-HydratedProclear Lenses

Hydrated and non-hydrated Proclear lenses were individually placed in 6ml glass vials containing 3 ml of 0.01 mole/liter of polystyrenesulfonate (PSS) having a molecular weight of 145K, 3K or 206 (monomer).After 48 hours the PSS concentration in each vial was measured by UVspectroscopy at 273.5 nm. The average for each condition (n=3) is shownin Table 4. The dry lens took up significantly more styrene sulfonatemonomer (Mol. Wt. 206) than the wet lens.

TABLE 4 Uptake (μg) PSS Mol. Wt. Dry Lens Wet Lens % Δ Dry vs Wet 145K301 308 −2%  3K 128 127 1% 206 110 92 16%

Example 6 Uptake and Release of Anionic Polymer by Proclear Lenses

Three non-hydrated Proclear lenses were individually placed in 6 mlglass vials containing 3 ml of 1000 μg/ml of 77K molecular weightpolystyrene sulfonate (PSS) in PBS, sealed, and autoclaved. A controlvial containing 3 ml of the PSS solution was also autoclaved. Theconcentration in each vial was measured by UV spectroscopy at 273.5 nmand the amount of PSS taken up by each lens was calculated as thedifference in PSS concentration between the control and test vials. Thelenses took up an average of 246 μg of the PSS. The lenses were testedfor release of PSS using the release assay substantially as described inExample 1, except that on day 1 the time points tested were 1 hr, 3 hr,5 hr, and 7 hr. The average cumulative release in μg and % is shown inTable 5.

TABLE 5 Cumulative release of 77K PSS 240 1 hr 3 hr 5 hr 7 hr 24 hr 48hr 72 hr 96 hr 168 hr hr 12 μg 28 μg 41 μg 50 μg 54 μg 58 μg 58 μg 60 μg64 μg 69 μg 5% 11% 17% 20% 22% 24% 24% 25% 26% 28%

Although the disclosure herein refers to certain illustrated examples,it is to be understood that these examples are presented by way ofexample and not by way of limitation. The intent of the foregoingdetailed description, although discussing exemplary examples, is to beconstrued to cover all modifications, alternatives, and equivalents ofthe examples as may fall within the spirit and scope of the invention asdefined by the additional disclosure.

A number of publications and patents have been cited hereinabove. Eachof the cited publications and patents are hereby incorporated byreference in their entireties.

The invention further provides:

1. A sealed package containing a contact lens immersed in a packagingsolution, said contact lens comprising a hydrogel comprisingphosphorylcholine groups; and an ionic agent that is polyionic orcomprises at least one guanidinium group or is both polyionic andcomprises at least one guanidinium group. Advantageously, the ionicagent is electrostatically bound to the phosphorylcholine groups of thehydrogel and releases the ionic agent upon being worn by a patient.

2. The package of 1, wherein the hydrogel comprises a hydratedpolymerization product of a monomer mixture comprising2-methacryloyloxyethyl phosphorylcholine (MPC).

3. The package of 2, wherein the monomer mixture comprises about 10 wt.% to 20 wt. % MPC.

4. The package of any one of 1-3, wherein the ionic agent comprises atleast one guanidinium group.

5. The package of any one of 1-3, wherein the ionic agent is selectedfrom epinastine, PHMB, polyarginine, epsilon polylysine, polystyrenesulfonate, and polyquaternium-55.

6. The package of any one of 1-4, wherein the ionic agent is polyionic.

7. The package of any one of 1-3, wherein the ionic agent comprises atleast two arginine groups.

8. The package of any one of 1-3, wherein the ionic agent comprises atleast two sulfonate groups.

9. A method of manufacturing a contact lens, said method comprising:

-   -   a) polymerizing a monomer mixture comprising        2-methacryloyloxyethyl phosphorylcholine (MPC) to provide an        non-hydrated lens-shaped polymerization product;    -   b) immersing the non-hydrated lens-shaped polymerization product        in a package containing a packaging solution comprising an ionic        agent; and    -   c) sealing the package. The ionic agent advantageously        electrostatically attaches to the phosphorylcholine groups on        the MPC.

10. The method of 9, wherein the monomer mixture comprises 10 wt. % to20 wt. % MPC.

11. The method of 9 or 10, wherein the ionic agent is polyionic orcomprises at least one guanidinium group or is both polyionic andcomprises at least one guanidinium group.

12. The method of 9 or 10, wherein the ionic agent is cationic.

13. The method of 9 or 10, wherein the ionic agent is anionic.

14. The method of 9 or 10, wherein the ionic agent is polyquaternium-55.

15. The method of 9 or 10, further comprising autoclaving the sealedpackage.

16. The package of any one of 1 to 8 above, or the contact lensmanufactured by the method of any one of 9 to 15 above, foradministering an ionic agent to ocular tissue of a patient in needthereof.

We claim:
 1. A method of manufacturing a contact lens, said methodcomprising: a) polymerizing a monomer mixture comprising2-methacryloyloxyethyl phosphorylcholine (MPC) to provide annon-hydrated lens-shaped polymerization product; b) immersing thenon-hydrated lens-shaped polymerization product in a package containinga packaging solution comprising an ionic agent; and c) sealing thepackage, wherein the ionic agent electrostatically attaches tophosphorylcholine groups on the MPC.
 2. The method of claim 1, whereinthe monomer mixture comprises 10 wt. % to 20 wt. % MPC.
 3. The method ofclaim 1, wherein the ionic agent is polyionic or comprises at least oneguanidinium group or is both polyionic and comprises at least oneguanidinium group.
 4. The method of claim 1, wherein the ionic agent iscationic.
 5. The method of claim 1, wherein the ionic agent is anionic.6. The method of claim 1, wherein the ionic agent is polyquaternium-55.7. The method of claim 1, further comprising: d) autoclaving the sealedpackage.
 8. A method of administering an ionic agent to ocular tissue ofa patient in need thereof, said method comprising administering thepatient an unworn contact lens immersed in a packaging solution andsealed in a package, said contact lens comprising: (a) a hydrogelcomprising integral phosphorylcholine groups; and (b) a releasable ionicagent electrostatically bound to the phosphorylcholine groups, whereinthe ionic agent is polyionic or comprises at least one guanidinium groupor is both polyionic and comprises least one guanidinium group.
 9. Themethod of claim 8, further comprising storing the contact lens after ithas been worn by the patient overnight in a storage solution comprisingadditional ionic agent which electrostatically binds to thephosphorylcholine groups thereby replenishing ionic agent releasedduring the previous wear by the patient.